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Neurodevelopmental outcome following Nitric Oxide Therapy for Persistent Pulmonary Hypertension in Term Newborn Infants

Three Part Question

In [a term infant with severe Persistent Pulmonary Hypertension of the Newborn] does [inhaled nitric oxide therapy] [improve the long term neurodevelopmental prognosis]?

Clinical Scenario

A 41 week gestation male infant, birth weight 4320g, is born by an emergency caesarean section at a District General Hospital for fetal distress and a poor fetal scalp blood gas. The infant is in poor condition at birth and requires intubation and ventilation. As the Tertiary Neonatal transport fellow you are called to transfer the infant to the Tertiary unit as he is hypoxic despite 100% oxygen and a peak pressure of 32. You calculate his oxygenation index to be 32. Your Consultant talks you through the use of the portable Nitric oxide equipment before you leave. You wonder what the long term neurodevelopment effect of Nitric oxide is in Term babies.

Search Strategy

Cochrane Library and Pubmed
Cochrane: Searching for nitric oxide and term infant – 1 systematic review (Finer)
PubMed: searching for Nitric oxide"[MeSH], Limits: Newborn: birth-1 month AND randomised controlled trial

Search Outcome

1 Cochrane systematic review
Pubmed - 6 relevant papers

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Lipkin PH
Mar 2002
Term infants with PPHNRandomized Controlled Trial (level 1b)Normal Motor outcomeC 82%, T 76% (n=35 & 87)No confidence intervals or actual p values given. Power calculation not described, but recruitment only half of aim. Follow-up publication of the Davidson paper
Normal Cognitive outcomeC 71%, T 69% (n=35 & 87)
Major Neurological abnormalityC 11%, T 14% (n=35 & 87)
Ellington M Jr et al
Jun 2001
Term or near term infants (>34 weeks gestational age) with PPHN.RCT (level 1b)Disabilityp=0.26 (T 9% v C 20%)Poor follow up rate (72% overall, 81% Treatment, 63% controls) and small numbers (25 controls followed up) No power calculation
Visual Disabilityp=0.3 (T 12%, C 3%)
Hearing or Speech Disabilityp=0.17 (T 11%, C 28%)
Developmental Quotient (Median)p=0.42 (T 102 v C 99)
Developmental Quotient <70p= 0.03 (T 0%, C 16%)
No authors listed (NINOS).
May 2000
Hypoxic infants >/=34 weeks' gestation and <14 days of ageRCT (level 1b)Cerebral PalsyC 9 (10.3%) v T 10 (11.8%)Secondary analysis of trial of INO for mortality. Inadequate numbers to show significant difference and no power calculation. Showed difference in seizures after discharge but multiple analyses and no use of the Bonferroni method to correct for this (may be a chance finding).
Seizures since dischargeC 13 (14.9%) v T 4 (4.7%), p=0.046
Blind in one or both eyesC 2 v T 2
Hearing normalC 59 (72%) v T 51 (68%)
Bayley scales MDI <70C 14 (19.2%) v T 21 (27.3%)
Mean Bayley Scale MDIC 87.0 (+/- 18.7) v T 85 (+/- 21.7)
Mean Bayley Scale PDIC 93.6 (+/- 17.5) v T 85.7 (+/- 21.2)
Davidson D et al
Mar 1998
Term infants (>37 weeks gestation, >2.5kg, <72 hours old) needing ventilation with 100% oxygenRCT (level 1b)Abnormal cranial ultrasoundcontrol 10% , Treatment 5%Failed to recruit anticipated number (studied only 155 of 320 aim) Neurologic sequelae studied until 28 days only, 1 year follow mentioned but not reported. Confidence Intervals or relative risks not given for outcomes
Abnormal neonatal neurologyControl 26%, Treatment 24%


Studies to date have not so far shown statistical evidence of abnormal development or poor neurological sequelae. At present insufficient subjects have been assessed for neurodevelopmetal outcomes. Further data is needed before a harmful effect of nitric oxide on neurodevelopment can be excluded.

Clinical Bottom Line

Insufficient evidence exists currently: a beneficial or harmful effect of nitric oxide on neurodevelopment cannot be excluded.


  1. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Oxford: Update Software. In: The Cochrane Library, Issue 3, 2003.
  2. Jacobs P, Finer NN, Fassbender K, Hall E, Robertson CM. Cost-effectiveness of inhaled nitric oxide in near-term and term infants with respiratory failure: eighteen- to 24-month follow-up for Canadian patients. Crit Care Med 2002;30(10):2330-4.
  3. Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. J Pediatr 2002;140(3):306-10.
  4. Ellington M Jr, O'Reilly D, Allred EN, McCormick MC, Wessel DL, Kourembanas S. Child health status, neurodevelopmental outcome, and parental satisfaction in a randomized, controlled trial of nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 2001;107(6):1351-6.
  5. No authors listed (NINOS). Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS). J Pediatr 2000 May;136(5):611-7.
  6. Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, Chang CT. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. Pediatrics 1998;101(3 pt 1):325-34.